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Molecules 2016, 21(9), 1236;

Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
College of Animal Science, South China Agricultural University, Guangzhou 510642, China
Author to whom correspondence should be addressed.
Academic Editor: Helena Vasconcelos
Received: 18 June 2016 / Revised: 7 September 2016 / Accepted: 10 September 2016 / Published: 15 September 2016
(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)
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In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3 µM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at the transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically-approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic stategy in ABCB1-positive drug resistant cancers. View Full-Text
Keywords: osimertinib; multidrug resistance; ABCB1; tyrosine kinase inhibitors osimertinib; multidrug resistance; ABCB1; tyrosine kinase inhibitors

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Zhang, X.-Y.; Zhang, Y.-K.; Wang, Y.-J.; Gupta, P.; Zeng, L.; Xu, M.; Wang, X.-Q.; Yang, D.-H.; Chen, Z.-S. Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells. Molecules 2016, 21, 1236.

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